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Title:When good synapses go bad: dendritic spine dysgenesis in a mouse model of Fragile X mental retardation
Author(s):Aldridge, Georgina
Director of Research:Greenough, William T.
Doctoral Committee Member(s):Greenough, William T.; Juraska, Janice M.; Korol, Donna L.; Ceman, Stephanie S.
Department / Program:School of Molecular & Cell Bio
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Fragile X Syndrome
dendritic spines
Gene Therapy
viral vector
Fragile X Mental Retardation Protein (FMRP)
mouse model
Abstract:Fragile X Syndrome (FXS) is the leading inherited cause of mental retardation, and the most common identified genetic cause of autism. Although many phenotypes have been associated with the disorder, arguably the most well-studied and interesting is a pattern of dendritic spine “dysgenesis”, found in patients and animal models of the disorder. Specifically, dendritic spines, thorn-like protrusions associated with synapses, appear “immature”: often exhibiting abnormal length and shape, and found in higher than typical density in many brain regions. The phenotype described is consistent with the hypothesis that deficient synaptic pruning results in the observed spine phenotype. However, directly testing this hypothesis is not possible using traditional methods because the history and fate of particular spines is unknown. Through the use of repeated in vivo imaging using 2-photon microscopy I was able to track the fate of individual spines over different periods of development on layer V dendritic tufts. Spine turnover, including both the formation of new spines and the elimination of existing spines, is enhanced in the Fmr1 knockout (KO) animals compared with wildtype (WT) controls. Furthermore, the increased population of transient spines in the KO mice are not sensitive to modulation by sensory experience, such as by chessboard whisker trimming. Newly formed and eliminated spines were found to be more immature appearing compared to stable spines, suggesting that these spines could contribute to the abnormal spine profile described in Fragile X. However, multiple experiments showed KO spines from the layer V dendritic tufts do not display the spine phenotype previously described for this region of neocortex. Instead, my analysis of spine morphology and dynamics in this region suggests that morphology and size are strong predictors of instability, but that in the KO mouse, there is some dysregulation of this relationship. Using lithium, a model pharmacological treatment for Fragile X, I was able to demonstrate that the dynamic, in vivo spine phenotype can be modulated in both WT and KO mice. Lithium caused increased turnover of spines, and may specifically lead to more elimination of spines in the Fmr1 KO in some contexts, potentially explaining the phenotypic rescue described for this drug in the literature. Finally, in order to test whether the spine phenotype could be modified in adult animals, I used recombinant adeno-associated viral vector (rAAV) to induce reexpression of FMRP in the brain. Analysis by Golgi staining showed that expression of FMRP altered the spine phenotype towards a profile resembling the phenotype in WT animals injected with control vector. Together, these findings support a dynamic model of the dendritic spine phenotype that is responsive to the current environment and context, rather than being subject to developmental constraints. This novel dynamic spine phenotype observed in Fragile X mice, including an increased population of labile dendritic spines and abnormal responsiveness to sensory modulation, will be an important target for pharmacological (or gene replacement) rescue, as it may represent the capacity and proclivity of the network to learn and change.
Issue Date:2012-02-01
Rights Information:Copyright 2011 Georgina Michelle Aldridge
Date Available in IDEALS:2012-02-01
Date Deposited:2011-12

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